LHPP promotes the intracellular reactive oxygen species accumulation and sensitivity of gastric cancer to cisplatin via JNK and p38 MAPK pathways

Background. Cisplatin is the first-line chemotherapy drug for the treatment of gastric cancer (GC) patients. However, GC patients who are resistant to cisplatin often do not benefit from it. Therefore, finding a key molecule that affects cisplatin sensitivity is expected to enhance the efficacy of cisplatin in GC treatment. Methods. The human GC cell lines SGC-7901 and BGC-823 were used. The protein chip array was used to screen the cisplatin-resistance genes from the complete response and non-complete response GC patients’ tissues, then, the differential gene expression analysis, GO function annotation analysis, and KEGG pathway enrichment analysis were performed. The GC tissue chip in the GEO database was analyzed to screen the target gene. Flow cytometry, Hoechst 33342 staining assay, Western Blot, MTT, tumor sphere formation, cell cycle, and apoptosis assays were performed to explore the effect of Phospholysine Phosphohistidine Inorganic Pyrophosphate Phosphatase (LHPP) on the apoptosis, stemness, and reactive oxygen species (ROS) accumulation of cisplatin-resistant GC cells treated with cisplatin. In vivo, the cisplatin-resistant GC cell lines transfected with pcDNA-LHPP or si-LHPP were injected subcutaneously into mice to construct GC subcutaneous xenograft GC models. Results. Based on protein chip array and bioinformatics analysis, it was found that LHPP is the core molecule in the cisplatin resistance regulatory network in GC, and its expression is down-regulated in GC cisplatin-resistant tissues and cells. In vitro and in vivo experimental results show that the up-regulated expression of LHPP is closely related to the increase in sensitivity of GC to cisplatin. Mechanically, we found that overexpression of LHPP may inhibit the activation of the JNK and p38 MAPK pathways, promote cisplatininduced ROS accumulation, suppress stemness, and enhance the sensitivity of GC to cisplatin. Conclusions. Up-regulation of LHPP may inhibit the activation of the JNK and p38 MAPK pathways, attenuate stemness, and enhance the accumulation of intracellular ROS, thereby promoting cisplatin-mediated GC cell apoptosis and enhancing cisplatin sensitivity

The p38 MAPK-regulated PKD1/CREB/Bcl-2 pathway contributes to selenite-induced colorectal cancer cell apoptosis in vitro and in vivo

AbstractSupranutritional selenite has anti-cancer therapeutic effects in vivo; however, the detailed mechanisms underlying these effects are not clearly understood. Further studies would broaden our understanding of the anti-cancer effects of this compound and provide a theoretical basis for its clinical application. In this study, we primarily found that selenite exposure inhibited phosphorylation of cyclic adenosine monophosphate (cAMP)-response element binding protein (CREB), leading to suppression of Bcl-2 in HCT116 and SW480 colorectal cancer (CRC) cells. Moreover, the selenite-induced inhibitory effect on PKD1 activation was involved in suppression of the CREB signalling pathway. Additionally, we discovered that selenite treatment can upregulate p38 MAPK phosphorylation, which results in inhibition of the PKD1/CREB/Bcl-2 survival pathway and triggers apoptosis. Finally, we established a colorectal cancer xenograft model and found that selenite treatment markedly inhibits tumour growth through the MAPK/PKD1/CREB/Bcl-2 pathway in vivo. Our results demonstrated that a supranutritional dose of selenite induced CRC cell apoptosis through inhibition of the PKD1/CREB/Bcl-2 axis both in vitro and in vivo

Identifying and analyzing novel epilepsy-related genes using random walk with restart algorithm.

As a pathological condition, epilepsy is caused by abnormal neuronal discharge in brain which will temporarily disrupt the cerebral functions. Epilepsy is a chronic disease which occurs in all ages and would seriously affect patients' personal lives. Thus, it is highly required to develop effective medicines or instruments to treat the disease. Identifying epilepsy-related genes is essential in order to understand and treat the disease because the corresponding proteins encoded by the epilepsy-related genes are candidates of the potential drug targets. In this study, a pioneering computational workflow was proposed to predict novel epilepsy-related genes using the random walk with restart (RWR) algorithm. As reported in the literature RWR algorithm often produces a number of false positive genes, and in this study a permutation test and functional association tests were implemented to filter the genes identified by RWR algorithm, which greatly reduce the number of suspected genes and result in only thirty-three novel epilepsy genes. Finally, these novel genes were analyzed based upon some recently published literatures. Our findings implicate that all novel genes were closely related to epilepsy. It is believed that the proposed workflow can also be applied to identify genes related to other diseases and deepen our understanding of the mechanisms of these diseases

MRI in the differential diagnosis of primary architectural distortion detected by mammography

PURPOSEWe aimed to evaluate the diagnostic accuracy of a combination of dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) and apparent diffusion coefficient (ADC) values in lesions that manifest with architectural distortion (AD) on mammography.METHODSAll full-field digital mammography (FFDM) images obtained between August 2010 and January 2013 were reviewed retrospectively, and 57 lesions showing AD were included in the study. Two independent radiologists reviewed all mammograms and MRI data and recorded lesion characteristics according to the BI-RADS lexicon. The gold standard was histopathologic results from biopsies or surgical excisions and results of the two-year follow-up. Receiver operating characteristic curve analysis was carried out to define the most effective threshold ADC value to differentiate malignant from benign breast lesions. We investigated the sensitivity and specificity of FFDM, DCE-MRI, FFDM+DCE-MRI, and DCE-MRI+ADC.RESULTSOf the 57 lesions analyzed, 28 were malignant and 29 were benign. The most effective threshold for the normalized ADC (nADC) was 0.61 with 93.1% sensitivity and 75.0% specificity. The sensitivity and specificity of DCE-MRI combined with nADC was 92.9% and 79.3%, respectively. DCE-MRI combined with nADC showed the highest specificity and equal sensitivity compared with other modalities, independent of the presentation of calcification.CONCLUSIONDCE-MRI combined with nADC values was more reliable than mammography in differentiating the nature of disease manifesting as primary AD on mammography

Regenerated woody plants influence soil microbial communities in a subtropical forest

10 páginas.- 4 figuras.- 3 tablas.- referencias.- upplementary data to this article can be found online at https://doi. org/10.1016/j.apsoil.2023.104890Forests are critical for supporting multiple ecosystem services such as climate change mitigation. Microbial diversity in soil provides important functions to maintain and regenerate forest ecosystems, and yet a critical knowledge gap remains in identifying the linkage between attributes of regenerated woody plant (RWP) communities and the diversity patterns of soil microbial communities in subtropical plantations. Here, we investigated the changes in soil microbial communities and plant traits in a nine hectare Chinese fir (Cunninghamia lanceolata; CF) plantation to assess how non-planted RWP communities regulate soil bacterial and fungal diversity, and further explore the potential mechanisms that structure their interaction. Our study revealed that soil bacterial richness was positively associated with RWP richness, whereas soil fungal richness was negatively associated with RWP basal area. Meanwhile, RWP richness was positively correlated with ectomycorrhizal (ECM) fungal richness but negatively correlated with the richness of both pathogenic and saprotrophic fungi, suggesting that the RWP-fungal richness relationship was trophic guild-specific. Soil microbial community beta diversity (i.e., dissimilarity in community composition) was strongly coupled with both RWP beta diversity and the heterogeneity of RWP basal area. Our study highlights the importance of community-level RWP plant attributes for the regulation of microbial biodiversity in plantation systems, which should be considered in forest management programs in the future.This work was funded by the National Key Research and Development Program of China (2021YFD2201301 and 2022YFF1303003), the National Natural Science Foundation of China (U22A20612), and the Key Project of Jiangxi Province Natural Science Foundation of China (20224ACB205003).Peer reviewe

Loss of COPZ1 induces NCOA4 mediated autophagy and ferroptosis in glioblastoma cell lines

Dysregulated iron metabolism is a hallmark of many cancers, including glioblastoma (GBM). However, its role in tumor progression remains unclear. Herein, we identified coatomer protein complex subunit zeta 1 (COPZ1) as a therapeutic target candidate which significantly dysregulated iron metabolism in GBM cells. Overexpression of COPZ1 was associated with increasing tumor grade and poor prognosis in glioma patients based on analysis of expression data from the publicly available database The Cancer Genome Atlas (P < 0.001). Protein levels of COPZ1 were significantly increased in GBM compared to non-neoplastic brain tissue samples in immunohistochemistry and western blot analysis. SiRNA knockdown of COPZ1 suppressed proliferation of U87MG, U251 and P3#GBM in vitro. Stable expression of a COPZ1 shRNA construct in U87MG inhibited tumor growth in vivo by ~60% relative to controls at day 21 after implantation (P < 0.001). Kaplan–Meier analysis of the survival data demonstrated that the overall survival of tumor bearing animals increased from 20.8 days (control) to 27.8 days (knockdown, P < 0.05). COPZ1 knockdown also led to the increase in nuclear receptor coactivator 4 (NCOA4), resulting in the degradation of ferritin, and a subsequent increase in the intracellular levels of ferrous iron and ultimately ferroptosis. These data demonstrate that COPZ1 is a critical mediator in iron metabolism. The COPZ1/NCOA4/FTH1 axis is therefore a novel therapeutic target for the treatment of human GBM.publishedVersio

Underexpression of Deleted in liver cancer 2 (DLC2) is associated with overexpression of RhoA and poor prognosis in hepatocellular carcinoma

<p>Abstract</p> <p>Background</p> <p>DLC2, a unique RhoGAP, has been recently identified as a tumor suppressor gene in hepatocellular carcinoma (HCC). However, the expression of DLC2 protein, and its relationship with RhoA in clinical hepatocellular carcinoma have not been studied. The aim of this study was to investigate the DLC2 protein expression and its correlation with expression of RhoA, as well as to evaluate the prognostic value of DLC2 for HCC patients.</p> <p>Methods</p> <p>Western blot and immunohistochemical staining were employed to detect DLC2 protein expression in 128 HCC specimens. The correlation between DLC2 protein expression and clinicopathologic outcome, and prognostic value of DLC2 for HCC patients were analyzed.</p> <p>Results</p> <p>HCC tissues revealed significantly lower level of DLC2 protein than pericarcinomatous liver tissues (PCLT). There was significant correlation between underexpression of DLC2 protein and cell differentiation. Meanwhile, underexpression of DLC2 protein was correlated with overexression of RhoA. Furthermore, HCC Patients with DLC2-negative expression showed a significantly poorer prognosis than those with DLC2-positve expression.</p> <p>Conclusion</p> <p>Our data strongly suggested that decreased DLC2 expression in HCC correlates with cell differentiation of HCC and overexpression of RhoA, underexpression of DLC2 is associated with poor prognosis in HCC patients.</p